Polyallylamine is a homopolymer of allylamine monomer obtained by polymerization of allylamine hydrochloride using a radical initiator such as 2,2′-azobis(2-methylpropionaimidine) dihydrochloride. Polyallylamine is used to form polyallylamine hydrochloride salts which are produced by polymerization of allylamine hydrochloride in presence of a radical initiator. Polyallylamine hydrochloride is a homopolymer of molecular weight ranging from 2000 to 100,000 Daltons. Polyallylamine and polyallylamine hydrochloride are highly soluble in water, which upon cross-linking with suitable N-alkylating reagents becomes water insoluble, and forms a water swellable polymer.
Cross-linked polyallylamine salts are found to be efficient anion exchange polymers that are insoluble in water. Because of this property, cross-linked polyallylamine salts evolved as good phosphate binders and/or bile acid binders without going into a solution form and thus polyallylamine salts are useful as a local acting drug administered to treat hyperphosphatamia and hyperlipidemia. The protonated polymeric amine groups of cross-linked polyallylamine interact with phosphate ions in the intestine. By binding with phosphate ions in the dietary tract, the cross-linked polyallylamine reduces absorption of phosphate and lowers phosphate levels in the serum. Sevelamer hydrochloride (approved by FDA and sold in the United States under the brand name Renagel®) is a cross-linked polyallylamine hydrochloride having a CH2-CHOH—CH2 group between two amino groups, wherein about 40% of the amine groups are protonated and associated with a chloride anion. Sevelamer hydrochloride contains about 18% chloride by weight, and when administered orally, the chloride anion is exchanged for phosphate anion in the gastro-intestinal (GI) tract thus reducing the phosphate level in the blood stream. The process of making polyallylamine hydrochloride cross-linked with epichlorohydrin (sevelamer hydrochloride) is disclosed in U.S. Pat. No. 4,605,701 (Harada et al.), U.S. Pat. No. 5,496,545 (Holmes-Farley et al.), U.S. Pat. No. 5,667,775 (Holmes-Farley et al.), U.S. Pat. No. 6,083,495 (Holmes-Farley et al.), U.S. Pat. No. 6,423,754 (Holmes-Farley et al.), U.S. Pat. No. 6,509,013 (Holmes-Farley et al.), U.S. Pat. No. 6,710,162 (Rea), U.S. Pat. No. 6,733,780 (Tyler et al.), U.S. Pat. No. 7,014,846 (Holmes-Farley et al.), U.S. Pat. No. 6,600,011 (McDonnell et al.), and U.S. Pat. No. 6,525,113 (Klix et al.) which are herein incorporated by reference. Additionally, in U.S. patent application Ser. No. 10/125,684 (Petersen et al.) now U.S. Pat. No. 7,541,024 (Petersen et al.), polyallylamine with reduced salt was used to prepare a cross-linked polyallylamine hydrochloride containing about 5 to 12% chloride, which is significantly lower compared to the sevelamer hydrochloride currently on the market as Renagel®. These processes are good for making a hydrochloride salt of the cross-linked polymer in the chloride form.
Colesevelam hydrochloride (approved by FDA and sold in the United States under the brand name Welchol®) is a modified cross-linked polyallylamine polymer containing polyallylamine base moiety having a CH2-CHOH—CH2 group between two amino groups, N-alkylated with a specific ratio of (6-trimethylammonium)hexyl group and decyl group. Colesevelam hydrochloride has almost all of its amines protonated and contains about 21% chloride by weight. Colesevelam hydrochloride is a high capacity bile acid binding polymer and is administered orally to treat hyperlipidemia. The process of making colesevelam is disclosed in U.S. Pat. No. 5,607,669 (Mandeville III, et al.), U.S. Pat. No. 5,679,717 (Mandeville III et al.), U.S. Pat. No. 5,693,675 (Mandeville III et al.), U.S. Pat. No. 5,917,007 (Mandeville III et al.), U.S. Pat. No. 5,919,832 (Mandeville III et al.), U.S. Pat. No. 6,066,678 (Mandeville III et al.), U.S. Pat. No. 7,101,960 (Mandeville III et al.), U.S. Pat. No. 6,433,026 (Mandeville III et al.) and U.S. Pat. No. 6,874,254 (Silvera et al.) which are herein incorporated by reference. These processes are also good for making a hydrochloride salt of the cross-linked polymer in the chloride form. In contrast, sevelamer carbonate is a salt of the cross-linked polymer in the carbonate form. Sevelamer carbonate (approved by FDA sold in the United States under the brand name Renvela®), which is yet another cross-linked polyallylamine polymer, having a CH2-CHOH—CH2 group between two amino groups containing bicarbonate anions, and is prescribed to treat hyperphosphatamia. According to the packaging insert of Renvela®, “Sevelamer Carbonate is an anion exchange resin with the same polymeric structure as sevelamer hydrochloride in which carbonate replaces chloride as the counterion. While the counterions differ for the two salts, the polymer structure itself the active moiety, is the same”. The advantage of administering sevelamer carbonate over sevelamer hydrochloride is that in the administration of sevelamer carbonate, the excess load of chloride ions is averted and helps to maintain bicarbonate level in the blood. According to the label and a review of literature for sevelamer carbonate, sevelamer carbonate is made by an ion exchange process using sevelamer hydrochloride, by displacing the chloride ions with carbonate ions. Though the Renvela® package insert states that the active moiety in sevelamer carbonate is same as that of sevelamer hydrochloride none of the listed examples disclosed in U.S. Pat. No. 5,496,545 (Holmes-Farley et al.), U.S. Pat. No. 5,667,775 (Holmes-Farley et al.), U.S. Pat. No. 6,509,013 (Holmes-Farley et al.), U.S. Pat. No. 6,858,203 (Holmes-Farley et al.), or U.S. Pat. No. 7,014,846 (Holmes-Farley et al.), describe the process of making sevelamer carbonate. None of the examples described in these patents, however, disclose the conversion of sevelamer hydrochloride to sevelamer carbonate.
The abstract of Indian Patent Application No. 1893/MUM/2006 (Milind et al.), discloses a process of making sevelamer carbonate by treating a suspension of sevelamer base with carbon dioxide. However, this reference does not disclose the conversion of sevelamer hydrochloride to sevelamer carbonate. The advantage of administering sevelamer carbonate over sevelamer hydrochloride is that the excess load of chloride ions is averted and helps to maintain bicarbonate level in the blood.
The present invention discloses a novel process of manufacturing sevelamer carbonate from a polyallylamine carbonate and/or bicarbonate chloride salt mixture directly without first making sevelamer hydrochloride and further converting to sevelamer carbonate. This novel process involves making the carbonate and/or bicarbonate salt of polyallylamine and then performing cross-linking with epichlorohydrin. This introduces carbonate and/or bicarbonate ions into the polyallylamine and helps to arrange the polyallylamine chain in the solution in such a way that the cross-linking reaction with epichlorohydrin can be controlled at a desired reaction rate. The process involves simple and fewer operations that are suitable for commonly available manufacturing equipment and working capacities. The invention further discloses a novel process of making colesevelam carbonate and/or bicarbonate salt mixture, and a process of making colestipol bicarbonate and/or bicarbonate salt.